The invention is related to obtaining the R(−)- and S(+)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide enantiomers, with a high degree of optical purity, by means of the separation of the diastereoisomeric salts which are formed from a mixture containing said enantiomers with an optically active acid, as well as to the development of a method which allows determining the degree of optical purity of said enantiomers once they are separated.
European patent EP 34432 discloses sulfamoyl-substituted phenethylamine derivatives exhibiting α-adrenergic blocking activity, useful as antihypertensive agents suitable for the treatment of congestive heart failure. Among said compounds is 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide (I),
one of the enantiomers of which, specifically the R(−)- enantiomer, known as Tamsulosin, is useful in the treatment of congestive heart failure and benign prostatic hypertrophy.
Prior studies have proven that the pharmacological action of the R(−)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide enantiomer, hereinafter R(−)-I, is up to 320 times greater than that of its S(+)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenenesulfonnamide enantiomer, hereinafter S(+)-I [Honda, K., Nakagawa, Ch., Terai, M., Naunyn-Schimiedeberg's Arch. Pharmacol. (1987), 336(3): 295–302; Honda, K., Nakagawa, Ch., Momose, N., J. Pharm. Pharmacol. (1987), 39(4): 316–18]. Therefore, it is necessary to obtain the optically pure R(−)-I enantiomer substantially free of the S(+)-I enantiomer. It is also necessary to have an industrial process for the production of the R(−)-I enantiomer.
European patent EP 34432 discloses a process for the preparation of said compound of formula (I) although it does not disclose the obtainment of its optical isomers.
U.S. Pat. No. 4,731,478 discloses in its examples a process for obtaining the R(−)-I and S(+)-I enantiomers from the condensation of R(−)- or S(+)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide with 2-(o-ethoxyphenoxy)ethyl bromide.
European patents EP 257787 and EP 380144 disclose a process for obtaining the R(−)-I enantiomer from the synthesis of the R(−)-5-((2-amino-2-methyl)ethyl)-2-methoxybenzene-sulfonamide chiral amine, in its optically pure form, and later condensation reaction by reductive amination or by nucleophilic substitution.
Until now, however, no reference has been found in the literature regarding methods for the resolution of compound (I).